ICL 3.7: Pathology of Atherosclerosis

Question 1

what are the 3 components of normal arteries?

Answer 1

1. endothelial cells
2. smooth muscle cells
3. extracellular matrixes = elastin, collagen, glycosoaminoglycans

Question 2

what are the 3 concentric laters of arteries?

Answer 2

1. intima

single layer of endothelial cells, minimal subendothelial connective tissue

2. media

smooth muscles (concentric layers), external elastic lamina, vasa vasorum

3. adventitia

nerve fibers, vaso vasorum

Question 3

what is the vascular wall’s response to injury?

Answer 3

intimal thickening!

trying to protect itself from further injury

Question 4

what are some of the major risk factors for atherosclerosis?

Answer 4

1. age
2. male gender
3. family history
4. genetic abnormalities

Question 5

how does gender effect atherosclerosis?

Answer 5

premenopausal, men are more likely

post-menopausal the women are at higher risk because they lose estrogen

in their 70s and 80s it’s the same risk

Question 6

how does genetics effect atherosclerosis?

Answer 6

1. diabets
2. HTN
3. familial hyperlipidemia

Question 7

which hyperlipidemia are familial?

Answer 7

type 2 and 3

Question 8

which factors can we control to limit atherosclerosis?

Answer 8

1. HTN
2. hyperlipidemia
3. smoking
4. DM
5. CRP**

BUT 20% of cardiovascular events occur without HTN, smoking, hyperlipidemia or DM so what does that leave? CRP!! It’s a devil

Question 9

what is hypercholesterolemia?

Answer 9

high serum cholesterol

high LDL delivers choleric to peripheral tissues!

HDL mobilizes cholesterol from the tissue and trsports it to the liver to be secreted in the bile

Question 10

what is CRP?

Answer 10

it’s an acute phase reactant synthesized in the liver and is downstream of a number of inflammatory triggers

it plays a role in inflammation and inflammation is present in all stages of atherosclerosis

assessment of systemic inflammation has become an important factor in risk stratification

CRP is a great marker of inflammation and has become the most simple and most sensitive to assess the risk of ischemic heart disease

Question 11

how does CRP play a role in the innate immune response?

Answer 11

1. opsonizes bacteria

2. activates complement

Question 12

what happens when CRP is secreted from cells within the intima?

Answer 12

1. activates local endothelial cells –> inflammatory cascade starts and then when the leucocytes (specifically monocytes) they start to produce cytokines which again enhance the inflammatory cascade
2. induces a prothrombotic state ):
3. increases the adhesiveness of the endothelium to leucocytes

Question 13

what does high sensitivity CRP predict the risk of?

Answer 13

1. MI
2. stroke
3. sudden cardiac death

high sensitivity CRP is the same as CRP but it’s our technological ability to detect minute amounts of CRP – so even tiny amouts of CRP means they’re at a higher risk for these adverse effects!

Question 14

what is hyperhomocystinemia?

Answer 14

elevated homocysteine

familial hyperhomocystinemia is associated with premature cardiovascular disease in teens and 20s

Question 15

what can cause hyperhomocystinemia?

Answer 15

1. low folate

2. low B12

Question 16

what is metabolic syndrome?

Answer 16

1. obesity
2. HTN
3. hyperlipdemia
4. DM

Question 17

what is lipoprotein a?

Answer 17

it’s an altered form of LDL

increased levels of it is associated with increased risk of coronary artery diseases and cerebrovascular diseases INDEPENDENT of total cholesterol and LDL levels!!!

Question 18

what are the hidden evil spirits that can cause atherosclerosis?

Answer 18

1. CRP
2. hyperhomocystinemia
3. obesity
4. lipoprotein a

Question 19

what levels of HTN put you at a higher risk of atherosclerosis?

Answer 19

BP higher than 160/95

BP lower than 140/90 has a lower incidence of atherosclerosis

Question 20

how does DM put you at a higher risk of atherosclerosis?

Answer 20

DM induces hypercholesterolemia which increases the incidence of atherosclerosis

Question 21

what happens when there’s endothelium injury?

Answer 21

increased adhesion molecule (VCAM1) is produced

VCAM1 attracts monocytes and they adhere to the endothelial

then monocytes migrate to the intimate and transform into macrophages and foam cells

macrophages start phagocytosis the lipids that we’ve been putting into our system and when they eat the lipids, the macrophages become foam cells

then platelets adhere and chemkines/cytokines are released from the macrophages, platelets and vascular cells which triggers inflammation

this leads to smooth muscle recruitment from the media to the intima and the smooth muscle proliferations and produced extracellular matrix!

Question 22

what do macrophages do?

Answer 22

monocytes are initially protective via phagocytosis but then they generate chemokines and also produce growth factor which leads to smooth muscle proliferation

they also produce toxic oxygen spices leading to oxidation of LDL in the lesions

Question 23

what is the initial cell in atherosclerotic lesions?

Answer 23

the foam cell that used to be a monocyte!!! aka macrophages

Question 24

what is the initial trigger in atherosclerosis?

Answer 24

endothelial cell activation

Question 25

what is the composition of the lesion seen in atherosclerosis?

Answer 25

it's called an atheroma or fibrofatty plaque in the intima it consists of: 1. cells including macrophages 2. core of lipid intracellular and extracellular choelsterol 3. fibrous cap of ECM including collagen elastic fibers

Question 26

what happens to the smooth muscle in the arteries during atherosclerosis?

Answer 26

it migrates from the media to the intima and proliferates! it also deposits ECM components and converts the fatty streaks to mature fibrofatty atheromas this is initiated by PDGF released from the platelets adheres to the endothelial cells

Question 27

how do atheromas evolve?

Answer 27

1. early intimal plaque *foam cells* of macrophage and SMC origin 2. advanced atheroma modified by SMCs synthesized collagen producing the *fibrous cap* --> fibrous caps are very dangerous because if the cap breaks off, it can become an embolism 3. disruption of the fibrous CAP with superimposed thrombus --> serious clinical events

Question 28

what is the big point in the pathology of atherosclerosis?

Answer 28

inflammation is the foundation of atherosclerosis!

Question 29

what is the morphology of atherosclerosis?

Answer 29

atherosclerosis starts as fatty lipid streaks filled with foamy macrophages the initial lesion is foam cells which are lipid filled macrophages then there is intracellular lipid accumulation in other cells, not just macrophages then there is formation of the fibrous cap

Question 30

what are the plaques in atherosclerosis composed of?

Answer 30

1. cells including smooth muscle cells, macrophages and T cells 2. ECM 3. intra and extracellular lipids

Question 31

what is a fibroatheroma?

Answer 31

an atheroma with a fibrotic core and calcification

Question 32

what are the complications that can be seen with atheromas?

Answer 32

1. ulcerated atheromas 2. thrombus formation 3. hemorrhage 4. aneurysmal dilation --> abdominal aorta! not the ascending aorta like with syphilis aortic regurgitation Marfans or severe HTN will have dissecting aortic aneurism

Question 33

a 55 year old baker is found to have a high sensitivity CRP on his routine annual checkup blood glucose, lipid profile is normal, not a smoker, very active and exercise regularly what is the meaning of the high sensitivity CRP and what else should be checked?

Answer 33

he's at a higher risk of CVD and cerebrovascular disease you need to check lipoprotein a levels!

Question 34

fibrous CAP

Answer 34

made of ECM

Question 35

LDL oxidation

Answer 35

CRP oxidizes LDL and triggers inflammatory cascade

Question 36

what maintains the vascular permeability barrier?

Answer 36

endothelium